9-Alkoxime decansic acid-{66 -lactones

ABSTRACT

Stereo-specific total synthesis of steroidal materials. 7Substituted 3-oxo-1-heptenes or variants thereof are reacted with 2-alkylcycloalkane-1,3-diones yielding 3-substituted 6a Beta alkyl-cyclopenta(f) (l) benzopyrans or naphtho (2,1-b) pyrans. These are then subjected to a selective catalytic hydrogenation followed by an introduction of a hydroxy, alkoxy or acyloxy group at the 4a-position to produce a 3-substituted 6a Beta ,6ahydroxy, alkoxy or acyloxy perhydrocyclopenta (f) (l) benzopyran or perhydro-naphtho (2,1-b) pyran. These latter compounds are then converted into 4- or 5-(3-oxoalkyl)perhydroindene-5-ones or perhydronaphthalene-6-ones which in turn can be converted to known steroidal materials by known methods.

States Patent [191 Unite Saucy i 1 "FJ-ALKOXIME DECANSIC ACID-A-LACTONES[75] inventor: Gabriel Saucy, Essex Fells, NJ.

[73] ,Assignee: Hoffmann-La Roche Inc., Nutley,

[22] \Filed: Mar. 13, 1974 [21] Appl. No.: 450,710

Related US. Application Data [52] U.S. Cl. 260/3435 \[51] C07D 309/30[58] Field of Search 260/3435 [56] References Cited UNITED STATESPATENTS 3,708,500 Ill/1973 Rosenberger et a1 260/3435 [4 1 July 29,1975

Primary ExaminerDonald G. Daus Assistant Examiner-Anne Marie T. TigheAttorney, Agent, or FirmSamuel L. Welt; Jon S. Saxe; George M. Gould[57] ABSTRACT Stereo-specific total synthesis of steroidal materials.7-Substituted 3-oxo-1-heptenes or variants thereof are reacted with2-a1kylcycloa1kane-1,3-diones yielding 3-substituted 6aB-alkyl-cyclopenta[f] [1] benzopyrans or naphtho [2,1-b] pyrans. Theseare then subjected to a selective catalytic hydrogenation followed by anintroduction of a hydroxy, alkoxy or acyloxy group at the 4a-position toproduce a 3-substituted 6a 8,621- hydroxy, alkoxy or acyloxyperhydrocyclopenta [f] [1] benzopyran or perhydro-naphtho [2,l-b] pyran.These latter compounds are then converted into 4- or 5-(3-oxoalkyl)perhydroindene-S-ones or perhydronaphthalene-6-ones which inturn can be converted to known steroidal materials by known methods.

1 Claim, No Drawings ll P-ALKOXIME DECANSIC ACID- A-LACTONES RELATEDAPPLICATIONS This application is a divisional of applicants copendingapplication Ser. No. 57,373, filed July 22, 1970 now US. Pat. No.3,816,458 which is a continuation-in-part of applicants co-pendingapplication Ser. No. 679,989, filed Nov. 2, 1967 now abandoned, which isa continuation-in-part of applicants co-pending application Ser. l\o.633,730, filed Apr. 26, 1967 now abaondoned, which was filed as acontinuation-in-part of applicants" co-pending application Ser. No.604,124, filed Dec. 23, 1966 now abandoned, which was filed as acontinuation-in-part of applicants co-pending application Ser. No.549,816, filed May 13, 1966 now abandoned. This application is also acontinuation-in-part of co'pending application Ser. No. 813,693, filedApr. 4, 1969 now abandoned, inventors Gabriel Saucy and MichealRosenberger, entitled, Preparation of 3-Oxo-l9- nor .N-Steriods froml-[3-substituted alkyl]desA Steriods.

BACKGROUND OF THE INVENTION Cyclopenta[f][l -benzopyrans and7H-naphtho[2,lb lpyrans are valuable as intermediates in the totalsynthesis of steriods. Total syntheses utilizing these compounds asintermediates are described in US. patent application of Gabriel Saucy:Ser. No. 549,816, filed Dec. 23, 1966 now abandoned; Ser. No. 604,124filed May 13, 1966 now abandoned; Ser. No. 633,730, filed Apr. .16, 1967now abandoned. Other related applications include Ser. No. 633,693,filed Apr. 26, 1967 now abaondoned.

DETAILED DESCRIPTION OF THE INVENTION This invention is concerned withcertain polycylic compounds and with processes for their synthesis. Moreparticularly, this invention relates to novelcyclopentalffll]-benzopyrans and 7Hnaphtho[2,lblpyrans, and to methodsfor their production. These compounds are useful as intermediates insyntheses of :steriods and D-homosteroids, respectively. In syntheses ofsteroidal materials steric considerations are of great significance. Themost used steroidal compounds are those having a C/D-trans ring junctionwith the substituent in the I3-position being in the,B-stereoconfiguration. The present invention provides a facile totalsynthesis of l3B-C/D-transsteroidal materials. This desirable result isobtained via a unique asymmetric induction with optical specificitypreserved in subsequent reaction steps.

In a major aspect, this invention is concerned with novelcyclopenta[f][1]benzopyrans having the tricythe nucleus and novelnaphtho[2,l-blpyrans having the tricyclic nucleus These novel compoundsare generally defined by the formula wherein Y is hydrogen; an alkylgroup of from 1 to 6 carbons; or a group of the formula R CH C(R R)CH(R, CH(R, wherein R when taken alone, is hydroxy or a conventionalhydrolyzable ether or ester group convertible to a hydroxy group byhydrolysis, R when taken alone is hydrogen, and R and R when takentogether, are 0x0 or a conventional hydrolyzable ketal group convertibleto an oxo moiety by hydrolysis; R is a primary alkyl group of from 1 to5 carbon atoms; R is hydrogen, lower primary alkyl, or lower acyl; R R RR and R are each independently hydrogen or lower alkyl; Z is carbonyl ora group of the formula R is hydrogen or lower acyl; R is hydrogen orlower aliphatic hydrocarbyl; T represents either a single or doublebond; U represents a single or a double bond and is a single bond when Tis a single bond; m is an integer having a value of from 1 to 2; n is aninteger having a value of from 0 to l and is 0 when T represents adouble bond and is l T represents a single bond; r is an integer havinga value of from O to l and is 0 when T is a double bond and 1 when T isa single bond; and s is an integer having a value of from 0 to l and is0 when U is a double bond and 1 when U is a single bond. As usedthroughout the specification and appended claims, the term hydrocarbylgroup denotes a monovalent substituent consisting solely of carbon andhydrogen and having from 1 to 20 carbon atoms; the term hydrocarbylenedenotes a divalent substituent consisting solely of carbon and hydrogencontaining 1 to 20 carbon atoms and having its valence bonds fromdifferent carbons; the term aliphatic with reference to hydrocarbyl orhydrocarbylene groups, denotes groups containing no aromaticunsaturation, but which can be otherwise saturated or unsaturated, i.e.,an alkyl or alkylene, or an aliphatic group containing olephinic oracetylenic unsaturation; the term alkyl group denotes a saturatedhydrocarbyl group, whether straight butylenedioxy)-butyl; alkoxybutyl,

or branched chain having 1 to 20 carbon atoms; the term primary alkylgroup denotes an alkyl group having its valence bond from a carbonbonded to at least two hydrogens; ther term acyl group denotes a groupconsisting of the residue of a hydrocarbyl monocarboxylic acid having 1to 18 carbon atoms formed by removal of the hydroxyl portion of thecarboxyl group; the term oxyhydrocarbyl" denotes a monovalent saturatedcyclic or acylic group consisting of carbon, hydrogen, and oxygencontaining only one oxygen in the form of an ether linkage; and the termlower, as applied to any of the foregoing groups, denotes a group havinga carbon skeleton containing up to and including eight carbons, such asmethyl, ethyl, butyl, tert.- butyl, hexyl, Z-ethylhexyl, vinyl, butenyl,hexenyl, ethynyl, ethylene, methylene, formyl, acetyl, Z-phenylethyl,benzoyl, methoxymethyl, l-methoxyethyl, and the like. The phraseologyconventional hydrolyzable ether or ester group convertible to a hydroxygroup by hydrolysis is meant to include ether groups such as loweralkoxy groups, e.g., methoxy, ethoxy, propoxy, t-butoxy (mostpreferable) and the like and lower oxyhydrocarbyloxy groups such astetrahydropyran-Z-yl-oxy, methoxymethyl-oxy, l-methoxy-ethyl-oxy and thelike; and ester groups such as acyl groups, e.g., formyloxy, acetyloxy,propionyloxy, pivaloyloxy, undecenoyloxy, benzoyloxy and the like. Thephraseology conventional hydrolyzable ketal group convertible to an oxomoiety by hydrolysis comprehends moieties of the formula OR O, OR S, ORN or SR S wherein R is alkylene having from 1 to 4 carbon I atoms.Exemplary moieties are 1,2-ethylenedioxy, 2,2-

dimethyl-l ,3-propylenedioxy, 1,2-ethylenedimercapto, 2,3-butylenedioxyand the like.

In the formulas presented herein, the various substituents on cycliccompounds are joined to the cyclic nucleus by one of three notations, asolid line indicating a substituent which is in the ,B-orientation(i.e., above the plane of the paper), a dotted line indicating asubstituent which is in the a-orientation (Below the plane of thepaper), or a wavy line indicating a substituent which may be either thea-or B-orientation. The position of R, has been arbitrarily indicated asthe ,B-orientation, although the products obtained in the examples areall racemic compounds unless otherwise specified.

Preferred compounds are those wherein Y is n-alkyl, especially methyl,3,3-(alkylenedioxy)butyl wherein the alkylenedioxy group, when takenwith the 3-carbon of the butyl radical; forms a dioxolane ring system,especially 3,3-(ethylenedioxy)-butyl and 3,3-(2, 3- 3-hydroxybutyl,3-tert.- especially 3-tert.-butoxybutyl, or 3-(tetrahydropyran-2-yloxy)butyl; R, is n-alkyl, especially methyl andethyl; and, when s has a value of l, the 9a- (when m is 1) or lOa-(whenm is 2) hydrogen is transoriented with respect to R Subgeneric to thetricyclic compounds of formula 1 are the 3-substituted-6aB-alky1-1,2,3,5,6,6a,7,8- octahydrocyclopenta [f][ l ]benzopyrans and the 3-substituted-6aB-alkyll ,2,5 ,6,6a,7,8 ,9-octahydro-3H-naphtho[2,l-b]pyrans (by alternate nomenclature 3-substituted-6aB-alkyll ,2,3 ,5,6,6a,8,9octahydro-7H-naphtho-[2,l-b]pyrans), hereinafter referred to as dienes, having theformula:

YCLT

wherein R R11, R Z, Y, and m are as defined above; and the3-substituted-6aB-a1kyl-4ahydroxyperhydrocyclopenta-[f][ l ]benzopyransand the 3substituted-6al3-alkyl-4a-hydroxyperhydronaphtho[2,l-b]pyransand their lower alkyl ethers and monoacyl esters, hereinafter referredto as perhydro compounds, represented by the formula:

N Ra e, l \(Cum wherein R R R R Z, Y, and m are as defined above,

Alternatively, the tricyclic compounds of formula I can be classifiedaccording to the nature of Y, which determines the utility of thecompounds of this inven tion. The first of these classes are the 3-alkylcompounds of the formula:

wherein R R R R Z, m, n, r, s, T, and U are as defined above the x is aninteger having a value of from O to 6, inclusive. These products areuseful as intermediates for the synthesis of members of a recentlydiscovered class of 9B, IOa-or retrosteroids, and also are useful asintermediates for the synthesis of 100:- :steroids, and other steroidalmaterials.

The second class of intermediates classified according to utility arethe 3-(4-substituted pentyl) compounds of the formula:

wherein R1 R2 R51 R11 R129 R141 R157 Z, 7 S, and U are as defined above;A is carbonyl or CR,-,. IR and R and R are as defined above. Thesecompounds, which are useful as intermediates for the synwherein R, R2,R55, R", R12, R, R15, Z, m, n, r, S, T, and U are as defined above.

2. The 3-[4,4-(ketal)pentyl]-substituted cyclopentabenzopyrans andnaphthopyrans of the formula:

thesis of l9-nor-steroids of the normal series, and other I steroidalmaterials, can be further classified as:

l The 3-(4-oxopentyl)-substituted cyclopentabenzopyrans andnaphthopyrans of the formula:

YCH2CHCHCHCH2CCH =CH2 h m 1, 2, 5, 9, 11, 12, 14, 15 T, and U are asdefined above; and both h are either sulfur or oxygen, or one h isoxygen and the other is sulfur or nitrogen. and

3. The 3-(4-hydroxypentyl)-substituted cyclopentabenzopyrans andnaphthopyrans and ethers thereof of the formula:

wherein R R R R R R R Z, m, n, r, s, T, and U are as defined above and Ris hydrogen, lower alkyl, lower acyl or lower oxyhydrocarbylulncompoundsof formula le-4, R as t-butyl is especially;-pre

ferred.

In a second aspect, this invention is concerned with a method forproducing the compounds of formula I via the following general reactionscheme:

-Continued YcH YCH2

wherein Y, R R R R Z, and m are as defined above; and B is hydrogen,lower alkyl or lower acyl.

Thus, the process of this invention comprises the general steps of l)condensation of a 7-hydroxy-l-alken- 3-one or a variant thereof (II), asdefined below, with a 2-alkylcycloalkane-l ,3-di0ne (Ill), as definedbelow, to produce diene (la); (2) saturation of the 990- orlO,lOa-double bond of diene (la) to produce monoene (lb); and (3)introduction of a hydroxy, alkoxy, or acyloxy group at the 4a-positionand a hydrogen atom at the 9bor lOb-position of monoene (lb) to produceperhydro compound (lc). It is to be understood that the foregoingreaction sequence is merely schematic in nature, and that each depictedstep can represent only one or more than one reaction, as will be morefully described herein It will be noted that the diene, monoene andperhydro compounds of this invention can bear a3-(4-oxopentyl)-substituent. When such a side chain is desired, it ishowever preferable to perform the reaction sequence with compoundshaving the 0x0 moiety of the 4-oxopentyl side chain in protected form.Protection can be effected by ketalization (to form lower alkylenedioxyor other hetero variants thereof), or by reduction to a hydroxy moietyoptionally followed by etherification or esterification. The oxo moietycan be regenerated at any intermediate stage as desired.

l-Alken-3-one compounds of formula ll are employed as one of thestarting materials for the foregoing reaction sequence. Illustrativeexamples of these 1- alken-3-ones-include 7-hydroxyl -octen-3-one,7-hydroxyl-nonen3-one, 7-hydroxyl -dodecen- 3-one,T-acetoxy-1-nonen-3-one, 7-benzoyloxy-lnonen-3-one,7-methoxy-lnonen-3-one, 7-benzyloxyl-nonen-3-one, l 1,11-ethylenedioxy-7-hydroxy-ldodecen-3-one,7,1l-dihydroxy-l-dodecen-S-one, lltert.butoxy-7-hydroxyl -dodecen-3-one,l l- [tetrahydropyran-2-yloxy)-7-hydroxy-1-dodecen- 13-one, and thelike.

The 7-hydroxyalken-3-ones of formula 11 above are readily synthesizedfrom (A) a glutaric acid anhydride,

(B) a E-alkylcyuohexane-l,3-dione, (C) a glutaralde- I0 hyde or (D) abutyrolactone, as is illustrated by the following sequences leading to7-hydroxynonen-3-ones:

R ""11 \IRIZ I 2 R12 R12 R ncl-ljcucucmci OH Iv in sequence A, asix-membered ring cyclic anhydride such as glutaric anhydride is reactedwith a lower alkanol, for example, ethanol, to produce a monoalkylglutarate half-ester. This half-ester is reacted with thionyl chlorideto produce the corresponding acid chloride, which in turn is reactedwith a dialkyl cadmium compound [(RCH Cd] to produce a5-alkylsubstituted S-oxopentanoate. This ketone is then hydrogenated inthe presence of a noble metal catalyst to form5-substituted-5-valerolactone. The lactone is reduced by reaction withdiisopropylaluminum hydride to form fa-substituted-tetrahydropyran-2-ol.The tetrahydropyranol is then reacted with vinyl magnesium bromide orchloride to form 7-substituted-l-heptenehydrogenation in the presence ofsodium hydroxide and Raney nickel followed by acidification, yields 5-substituted-5-valerolactone.

Sequence C involves reacting a 1,5-alkylenedial such as glutaraldehydewith a Grignard reagent of the formula YCH MgX wherein Y is as definedabove and X is bromine or chlorine to form a6-subsituted-tetrahydropyran-Z-ol. This reaction and the productsobtained thereby re described in greater detail in United States patentapplication of David A. Andrews and Gabriel Saucy, Ser. No.

633,693, filed Apr. 26, 1967, now abandoned entitled 6-SUBSTITUTEDTETRAl-IYDROPYRAN-Z-OLS AND PROCESS FOR THEIR PRODUCTION.

Sequence D comprises reacting, for example, butyrolactone with thionylchloride in the presence of zinc chloride to produce a 4-chlorobutyricacid chloride. The acid chloride is reacted with the dialkyl compound[(RCl-l Cd] as defined above to produce 5-substituted-1-chloropentan-4-one. The chloroketone, in the form of itsketal, for example, the ethylenedioxy ketal, is reacted with magnesiumto form 4 (ethylenedioxy)-5-substituted pentyl magnesium chloride. ThisGrignard reagent is reacted with acrolein to yield, upon hydrolysis,8-substituted-3-hydroxyocten- 7-one. This hydroxy ketone is reduced to7-substitutedl-heptene-3,7-diol by reaction with lithium aluminumhydride, and the diol converted to 7-substituted-7- hydroxyhpeten-3-oneby reaction with manganese dioxide.

Because of the susceptibility of the vinyl group of the7-hydroxy-l-alken-3-one to oxidation, it is desirable, although notessential, that this compound be converted to more stable variants, suchas those of the formula:

wherein R R Y and B are as defined above; and R is chloro, hydroxy,lower alkoxy, lower hydrocarbylamino or di(lower hydrocarbyl)amino.Variants of formula Ila and methods for their preparation are describedin detail in my United States patent application Ser. No. 604,124, filedDec. 23, 1966, now abandoned entitled a-OLEFINS.

As exemplary, these compounds of formula Ila are readily produced fromthe vinyl ketones of formula II by known techniques. For example,l-chloro-7- hydroxyalkan-3-ones are obtained by the anti- Markownikoffreaction of the vinyl compound with hydrogen chloride in known manner.l-Hydroxy and 1- alkoxy derivatives are obtained by the base-catalyzedreaction of water or a lower alkanol, for example, methanol, with thevinyl ketone. Additional derivatives are formed by the reaction of thevinyl ketone with a mono(lower hydrocarbyl) or di(lower hydrocarbyl)-amine to form the Mannich base 1(lower hydrocarbyl)amino or l-di(lowerhydrocarbyl)amino- 7-hydroxyalkan-3-one. A particularly advantageousprocedure is to oxidize a hydroxy vinyl compound of formula IVa withmanganese dioxide in the presence of such an amine. In some instances,particularly in large scale commercial operation, it may be desirable tocon vert the Mannich base to its crystalline acid addition salts,particularly quaternary ammonium salts. All of the chloro, hydroxy,alkoxy, and aminoalkanones yield the aklenones of formula I] under theconditions of the condensation with the 2-alkylcycloalkane-1,3-dione.

The compounds of formula II can be used in the form of still anothervariant. This is the cyclized variant comprising a cyclic hemiketal,i.e., Z-tetrahydropyranol of the formula:

wherein Y is as defined above and R is lower hydrocarbylamino ordi(lower hydrocarbyl)amino. The variants of formula Ilb can be preparedfrom compounds of formula II by reaction with the same reactants as areused to produce those compounds of formuls Ila wherein R is lowerhydrocarbylamino or di(- lower hydrocarbyl)amino. As is apparen, thosecompounds of formula Ila wherein R has the aforesaid meanings and thecompounds of formula Ilb are isomers. These isomers exist in the form ofa ketone of formula IIa or in the form of the cyclic hemiketal of formula Ilb or as an equilibrium mixture of the two forms, Whether aparticular Mannich base of formula Ila exists in that form or thehemiketal form or in an equilibrium mixture consisting primarily of oneor the other will depend upon the environmental conditions in which itis placed, such as temperature, solvent and pH of reaction medium, aswell as the particular meaning of Y and R or R Either form is useful forthe purposes of this invention since these isomers are used in areaction with compounds of formula III, infra, and either the acrylicform of formula Ila or the cyclic hemiketal form of formula Ilb isuseful for this purpose. A particular advantage of the cyclic form isits greater stability as compared with the acyclic form and also ascompared with the vinyl ketones of formula II. In order to obtain thecyclic form it is essential that in the compound of formula IIa, B ishydrogen. Acidic conditions shift the equilibrium away from the cyclicform. Use of an optically active amine, e.g., phenylethylamine, offersthe advantage of resolving the compound, for example, via saltformation, to give an optically pure isomer of formula Ila or III; whichis then used in the remainder of the reaction sequence of this inventionand when coupled with the unique asymmetric induction and preservationof optical specificity thereof offers a facile route to optically puresteroidal materials.

In a further aspect of this invention optically active compounds offormula Ilb where Y is 3-oxobutyl are prepared from optically activeprecursors according to thefollowing reaction sequence:

13 where R is lower alkyl; and R R and R are as above.

As indicated an optically active 9-oxo-decanoic acid iS-lactone offormula XXl is treated with a lower alkoxy amine or an acid additionsalt thereof. e.g.. a mineral acid salt such as the hydrochloride,hydrogen sulfate. hydrobromide and the like to form the correspondinglower alkoxy, imino compound XXII. A preferred lower alkoxyamine forthis purpose is methoxyamine. most preferably in the form of itshydrochloride salt. This reaction is conducted at a temperature in therange of from about l to 50C.. most preferably in the range of fromabout 25 to 30C. A solvent may be employed to facilitate the course ofthe reaction. Preferred solvents include organic nitrogen bases such asfor example, pyridine, triethylamine, dimethylamine, trimethylamine andthe like. After completion of the reaction wherein a mineral acid saltof the lower alkoxyamine is employed it is desirable to add a basicorganic amine to the reaction mixture to neutralize the acid produced.Suitable basic organic amines for this purpose include the tertiaryamines. e.g.. trialkylamines such as triethylamine.

In the second step of this sequence the keto lactone XXll is treatedfirst with vinyl Grignard, e.g., vinyl magnesium bromide or chloride inan ethereal solvent, e.g., tetrahydrofuran at a temperature in the rangeof from about 0 to 70C; preferably in the range of from about 45 to 55C.The resulting intermediate having the following tautomeric structure.

where R R and R are as above is then treated with a lowerhydrocarbylamine or a di( lower hydrocarbyl)amine, cg, diethylamine inan ethereal solvent, e.g., diethyl ether at a temperature in the rangeof from about 0 to 50C.. preferably at about room temperature to yieldan intermediate of the formula O.ll A a i lN A where R R R, and R are asabove.

The intermediate oxime compound XXIV when treated with dilute aqueousacid, such as aqueous mineral acid, eg. 2N sulfuric acid is hydrolyzedto the ketone with concomitant purification of the amine to yield thedesired compound of formula ll-bl This acid treatment step isconveniently carried out in the presence of a suitable inert organicsolvent, preferably a ketonic solvent such as acetone. at a temperaturein the range of from about 0 to 50C., preferably in the range of fromabout 20 to 30C., e.g., C.

lt should be noted that intermediate compounds XXllI and XXlV need notbe isolated or otherwise purified during the aforesaidtransformations'but can be utilized in crude form for further steps.

The optically active 9-oxo-decanoic acid B-lactone of the indicatedconfiguration may be prepared from racemic 5,9 -dioxodecanoic acid bymicrobiological reduction followed by lactonization. This procedure,which is not part of the present invention, is described in detail inUS. Pat. Application Ser. No. 57,371, now US. Pat. No. 3,657,070,MICROBIOLOGICAL PREPARATION OF OPTICALLY ACTIVE 9-OXO-S(S)-HYDROXY-DECANOIC ACID AND THE LACTONE THEREOF, inventors JuliusBerger and Michael Rosenberger.

As is indicated above, the 7-hydroxy group of the 7- hydroxyalkanone offormula II or Ila can be esterified or etherified for the condensationreaction with the cycloalkanedione. These reactions can be effected inknown manner. For example, the 7-hydroxyalkan- 3-one can be reacted witha carboxylic acid or an acid chloride to produce an ester, or can beconverted to an ether by either (l) preferably, known acid catalyzedetherifications, e.g., with isobutylene or dihydropyran 0r (2)conversion of the 7 hydroxyalken-3-one to its sodium salt followed byreaction of the salt with an alkyl halide. In the event R is hydrogen,this hydroxl group is also etherified or esterified.

The starting material of formula II or variant thereof can either beused in racemic form or in optically active form. When used in opticallyactive form, the 7S- antipode is preferred for reasons more fullyexplained below.

The second reactant employed in the condensation -wherein R and m are asdefined above. These compounds are known compounds and description oftheir synthesis is accordingly unnecessary. Suitable compounds includeZ-methylcyclopentane-l.3-dione, 2- ethylcyclopentanel ,3-dione,Z-propylcyclopentane- 1,3-dione, Z-butylcyclopentane-l ,3-dione,Z-methylcyclohexane-l,3-dione, and the like.

The conditions for the condensation of ketone (ll) or variant (lla, llbor llb-l with cyclic dione (lll) are not narrowly critical, although itis preferred particularly when the acyclic ketone is charged as thevinyl ketone, that a non-oxidizing atmosphere, e.g., nitrogen or argon,be employed, It is further preferred that an antioxidant, for example,phenolic compounds such as hydroquinone, be present. Furthermore, thereaction can be conducted in the absence or presence of acid or basepromoters. Suitable basic promoters include those heretofore known topromote the Michael condensa tion, including inorganic bases, forexample, alkali metal hydroxides, such sodium hydroxide or potassiumhydroxide, and organic bases, including alkali metal alkoxides, forexample, sodium or potassium methoxide or ethoxide, and ammoniumhydroxides, particularly benzyltrialkylammonium hydroxide. A preferredclass of base promoters are the amines, especially tertiary amines andmost preferably pyridine-type compounds such as pyridine and thepicolines. Acid promoters which can be employed include organiccarboxylic acids such as acetic acid or benzoic acid; organic sulfonieacids such as p-toluenesolfonic acid; and mineral acids such as sulfuricacid, phosphoric acid, hydrochloric acid, and the like. The amount ofpromoter employed is not narrowly critical and can vary from catalyticamounts to molar amounts.

YCH CHCHCHCH vcH The ratio of ketone (II) or variant (lla, llh orll-b-l) to cyclic dione (III) is not narrowly critical, althoughapproximately equimolar amounts are preferred. Although there is noparticular advantage to the use of excesses of either reactant, thecycloalkanedione can be more readily employed in excess because, due togeneral low solubility in known organic solvents, unreactedcycloalkanedione can be easily recovered from the reaction mixture.

The reaction temperature is not critical and can vary from roomtemperature or below to reflux temperature or higher. The condensationis preferably conducted in the presence of an inert solvent to insure afluid reaction mixture and uniform reaction temperatures. Primaryalcohols are not desirable due to their tendency to react withvinylketones. Suitable solvents include tertiary alcohols such astertpbutanol; aliphatic and aromatic hydrocarbons such as cyclohexane,hexane, octane, benzene. xylene toluene, and the like; ethers such asdiethyl ether, tetrahydrofuran, and the like; chlorinated hydrocarbonssuch as carbon tetrachloride, chloroform, and the like; as well asdipolar aprotic solvents such as dimethylsulfoxide and the N,Ndisubstituted amides such as dimethylformamide or dimethylacetamide.

The product of the condensation, depending upon the nature of vinylketone or variant (ll, Ila, llb or ll-bl and/or the reaction promoteremployed, can be one or more of the compounds having the formulae:

lu-l

methods for the chemical reduction of a ketone, e.g., by reaction ofdienone (Ia-l) with an alkali metal or Group III-metal reducing agent.By the term alkali metal, as employed herein. is meant a Group l-metalwherein R R R B, Y, and m are as defined above.

When vinyl ketone (II) is a 7-alkoxyor 7-acyloxy compound, the productwill be a compound of formula IV. However, when the vinyl ketone is a7-hydroxy compound, or the reaction conditions are sufficient to converta i -alkoxyor 7-acyloxy group, if present, the product will depend uponthe promoter.

When the promoter is an acid or a relatively weak base. such aspyridine, or when no promoter is employed at all. the reaction productobtained from the T-hydroxy vinyl ketone is the diene, i.e., tricyclicenol ether Ila-l When a strong base, such as sodium or potassiumhydroxide, is employed a promoter, a crystalline product having theformula VI is isolated, although compounds of formulae IV and V are alsopresent in the reaction mixture. However, the compounds of formulae IV,V and VI, upon treatment with an acid, such as acetic acid,para-toluene-sulfonic acid, or sulfuric acid, readily form the diene,i.e., tricyclic enol ether tjla-l t. It should also be noted that theconversion of the acyloxy or alkoxy groups of compound (IV) to a hydroxygroup in an acidic medium is accompanied by cyclization to enol ether(Ia-l The condensation of a vinyl ketone of formula II or a variantthereof of formula Ila or Ilb with a cycloalkanedione of formula III isone of the key features of this reaction. It is in this condensationthat specific stereochemical induction at one member of the criticalCID-ring junction of the eventual steroidal product occurs. Thus, thisinvention is particularly advantageous in that it involves a uniqueasymmetric inductin. Thus, the products of the condensation, i.e., thedienones of formula lla-l, have at least two asymmetric centers atpositions .3 and 6a permitting theoretically of two racemates or fouroptical antipodes. However, as a result of the condensation of thisinvention, when using a racemic starting material of formulas ll, lla orllb wherein IR and R are both hydrogen only a single racemate of formulala-l results and when using an optically active starting material offormulas ll, Ila, llb or lIb-l wherein R and R are both hydrogen only asingle optical antipode of formula la-l results. It has further beenfound that when starting with a compound of formula II or lla with a7Sstereocontiguration or of formula llb with correspondingstereoconfiguration there is obtained the more desirable opticalantipode of formula la-l having a 6aB-stereoconfiguration. Thus, toprepare steroidal materials having the more desired l3t3-stercoconfiguration by the synthesis of this invention one caneither start with the antipode of formula II, Ila, III; or IIh-l, whichcan be prepared by resolving a racemic compound of formula II, Ila orllb, or one can resolve at some intermediate stage subsequent to thecondensation with a cycloalkanedione of formula III or one can resolvethe end-product steroidal material. In any event, the unique asymmetricinduction concurrent to the condensation of this invention renders theobtention of a single optical antipode as an end-product more facile.The simultaneous formation of the dienol ether of formula Ia-l withunique asymmetric induction is a special advantage of this invention.

The dienes of formula la in the presence of water and acid, e.g.,sulfuric acid in acetone, aqueous acetic acid or aqueous hydrochloricacid in dioxane, undergo aid hydrolysis to form indenones of the formulawherein R R R Y and 111 have the same meaning as above. The indenones offormula Ia are themselves cnvertible to compounds of formula Ia viadehydration, for example, via acid catalyzed azeotropic distillation inbenzene. Suitable acid catalysts are p'toluenesulfonic acid, potassiumbisulfate, boron trifluoride etherate and the like. This reversiblehydrolysis of compounds of formula la is useful in their preparation andpurification. Thus, in instances where the direct purification ofcompounds of formula la is difficult it is often more facile tohydrolyze the compound of formula Ia to a compound of formula Ia, whichcan then be puritied, for example, by chromotography, and subsequentlybe reconverted to the desired compound of formula Ia via dehydration.

The ketodienes of formula Ia-l are readily converted to thecorresponding 7B-alcohols and their esters as represented by theformula:

orig YCH:

wherein Y, R R R R and m are as previously defined, by the sequence ofreactions comprising reduction of the ketone to the alcohol and, ifdesired. subsequent esterification.

The reduction can be effected by any of the known having an atomicnumber of from 3 to 19, inclusive, i.e.. lithium, sodium, and potassium,Group III-metals include those having atomic numbers of from 5 to l3,inclusive, i.e., boron and aluminum. Illustrative examples of thesereducing agents include an alkali metal, preferably lithium or sodium,in liquid ammonia or a liquid aliphatic amine; tri(loweralkoxy)-aluminum compounds such as triisopropoxyaluminum; di(loweralkyl)-aluminum hydrides such as diethylaluminum hydride anddiisobutylaluminum hydride; alkali metal- Group Ill-metal complexhydrides such as lithium aluminum hydride, sodium aluminum hydride, andsodium borohydride; tri(lower alkoxy)alkali metal-Group III- metalcomplex hydrides such as trimethoxy lithium aluminum hydride andtributoxy lithium aluminum hydride; diisobutyl aluminum hydride and thelike. The alkali metalGroup Ill-metal complex hydrides are preferred asreducing agents, with the nonalkaline reagents, such as lithium aluminumhydride, being especially preferred.

This reaction is effected in any suitable inert reaction medium, such ashydrocarbons, e.g., cyclohexane, benzene, toluene, and xylene; ethers,e.g., diethyl ether, diisopropyl ether, and tetrahydrofuran. Proticsolvents, such as water or alcohols, should not be employed when lithiumaluminum hydride is the reducing agent, but can be employed with sodiumborohydride.

The remaining reaction conditions are not narrowly critical, although itis generally preferred to effect the reduction at reduced temperatures,below about room temperature (about -25C. Temperatures in the range offrom about 0C. to about room temperature are normally employed.

In the reduction of a dienone of formula Ia-l to a die nol of formulalu-2 any keto group in the side chain symbolized by Y is simultaneouslyreduced and any aeyloxy group is hydrolyzed, in both cases yielding acorresponding hydroxy group. Any such side chain hydroxy group can beconverted to an oxo moiety by treatment with conventional oxidizingmeans such as manganese dioxide. It is, however, preferable to usestarting materials with etherified hydroxy moieties or ketalized oxomoieties in the side chain since these are unaffected by the reduction.

The free alcohol is recovered from the reaction mixture after treatmentof the mixture with acid. The alcohol can be esterified in known manner,for example, by base-catalyzed reaction with a carboxylic acid halide orcarboxylic acid anhydride. Illustrative bases include inorganic basessuch as sodium hydroxide and potassium hydroxide and organic bases sucha sodium alkoxide or an amine, especially a tertiary amine, and moreparticularly, pyridine and the pieolines.

The ketodienes of formula la-l can also be converted to their7B-hydroxy-7a-hydrocarbyl derivatives represented by the formula:

wherein Y, R R,,, R R and m are as previously defined and R is lowerhydrocarbyl by reaction of the ketodiene with a Grignard reagent of theformula:

w g vn wherein R is as previously defined and X is a halogen having anatomic number of from 17 to 35, inclusive (i.e., chlorine or bromine).

This Grignard reaction is conducted in known manner. For example, theGrignard reagent is prepared by reacting a hydrocarbyl halide withmagnesium in an ether reaction medium, for example, ethyl ether ortetrahydrofuran, at elevated temperature, generally in the range of fromabout 40 to about C. The ketodiene (Ia-l) is then added to the Grignardsolution at about room temperature, although higher or lowertemperatures can be employed. The resulting reaction product ishydrolyzed to produce the free alcohol, which can be esterified asdiscussed above.

Alternatively, the alcohols can be prepared by reaction of ketodiene(Ia-l with a hydrocarbyl alkali metal compound such as methyl lithium,sodium acetylide, potassium acetylide, and the like.

If a dienone of formula Ia-l is to be converted to a diene of formulaIa-3 then a starting material of formula Ia-l wherein the side chain Yincludes an oxo group should not be used. Also, during the course ofsuch conversion any ester moieties present in the side chain will behydrolyzed.

Illustrative examples of the dienes represented by formulae Ia-Z andla-3 include 3,6aB-dimethyl-7/3- hydroxy-l,2,3,5,6,6a,7,S-octahydro-cyclopenta[f][ I- lbenzopyran;3,6aB-diethyl-7B-hydroxyl,2,3,5,6,6a,7,8-octahydrocyclopenta[f]I l]benzopy- 3-ethyl-6aB-methyl-'lB-acetoxy-l ,2,3,5,6,6a,7,8-

ran; octahydrocyclopenta[f][ l ]-benzopyran; 3-ethyl-6aB'methyl-7B-benzoyloxy-l ,2,3,5,6,6a,7,8-

octahydrocyclopentalf][ l lbenzopyran; 3-ethyloctahydrocyclopental f]{ llbenzopyran; 3,7a-diethyl- 6aB-methyl-7Bhydroxy-l 2,3,5 ,6,6a,7 ,8-octahydrocyclopenta[f][ l lbenzopyran; 3-ethyl-7B-hydroxy-oafi-methyl-7oz-vinyl-I ,2,3,5,6,6a,7,8-octahydro-cyclopenta[f]l I lbenzopyran;3-ethyl-7aethynyl-7,8-hydroxy-6aB-methyl-l ,2,3,5,6,6a,7,8octahydrocyclopenta[f][ l ]benzopyran; 7/3-acetoxy-3ethyl-oafi'la-dimethyl-l ,2,3,5,6,6a,7,8- octahydrocyclopenta[f][ l]benzopyran; 3-ethyl-7B- hydroxy-6aB-dimethyl-I ,2,3,5,6,6a,8,9octahydro-7H- naphthol 2, I b lpyran; 7,8-hydroxy-6al3-methyl-3-(4-oxopentyl)-l,2,3,4,5,5a,7,8- octahydrocyclopenta[f][ l lbenzopyran',6aB-ethyl-7B- hydroxy-3-(4-oxopentyl)-l,2,3,5,6,6a, 7,8-octahydrocyclopenta[f][ l lbenzopyran; 3-l(4,4-ethylenedioxy)pentyl]-7B-hydroxy-6aB-methyll,2,3,5,6,6a,7,8-octahydrocyclopenta[f]Illbenzopyran; 3-l4,4-(2,3')-butylenedioxy-pentyll-oafi-ethyl-7B-hydroxy-l ,2,3,5,6,6a,7.8- octahydrocyclopenta[f][ l l-benzopyran;butoxypentyl)-7B-hydroxy-oaB-methyll,2,3,5,6.oa,7.S-octahydrocyclopenta[f][ l lbenzopyran; 3-( 4-t-butoxypentyl)-6aB-ethyl-7B-hydroxyl,2.3,5,6,6a,7,8-octahydrocyelopentalf][ llbenzopyran;7B-hydroxy-3-(4-hydroxypentyl)-6a,B-methyll,2,3,5,6,6a,7,8-octahydrocyclopcnta[flll lbenzopyran and the like.

The second step of the general synthesis of the tricyclic compounds ofthis invention comprises conversion of the dienes of formula In to themonoenes of formula lb by catalytic hydrogenation. Suitable catalysts include the noble metals, such as platinum. palladium, rhodium, and thelike, as well as Raney nickel and other hydrogenation catalysts. Thesecatalysts can be employed in the form of the metal alone, or can be deposited on suitable support materials, such as carbon, alumina, calciumcarbonate, barium sulfate. and the like. Palladium and rhodium arepreferred as catalysts. The hydrogenation is preferably conducted in thepresence of inert solvents such as hydrocarbons, alcohols. ethers, andthe like. The reaction conditions of pressure and temperature are notnarrowly critical, and normally a hydrogen pressure of about oneatmosphere and a temperature of about room temperature are employed.These ambient conditions are generally preferred to avoid significanthydrogenation of the la9b( lObt-double bond, although more severeconditions, for example, up to about 100C. and up to about 100atmospheres, can be employed if desired. The hydrogenation medium can beacidic, neutral, or basic, as may be desired, although neutral media,such as hydrocarbons, e.g., toluene or hexane, or basic media, such asan alcoholbase, e.g., methanol-sodium hydroxide, mixture are preferredfor best results. in general, hydrogenation of the diene of formula Ialeads to the corresponding monoene of formula lb. However, in the eventR is an unsaturated hydrocarbyl radical, the hydrogenation, in additionto hydrogenating the ring double bond, also hydrogenates the7a-hydrocarbyl substituent, converting it to an alkyl group.

Via the aforesaid catalytic hydrogenation C/D-trans compounds are formedin a major proportion when hydrogoenating a diene of formula la-Z. Thismethod thus provides an advantageous synthesis of C/D-trans steroidalmaterials. When hydrogenating a diene of formula Ta-l. C/D-cis compoundsare formed in a major proportion. This method thus provides anadvantageous synthesis of C/D-cis steroidal materials.

Compounds wherein Z is carbonyl, as represented by the formula:

Ib-l

wherein Y. R Rn, R and m are as previously defined, can be converted tothe corresponding alcohols or esters of the formula:

wherein Y, R,, R R R and m are as previously defined,

.or to the 7,8-hydroxy-7-a-hydrocarbyl compounds of the formula:

wherein Y, R R R R R,;; and m are as previously defined,

by the techniques discussed above regarding the dienes of formula la.

When Z is carbonyl and the hydrogenation is effected under basicconditions, there is a tendency toward the production of predominantlythe 6a/9a( lOa)-ciscompound; that is, the hydrogen atom in the 9a( 10a)-position of formula lh-l is predominantly in the B-orientation. Whenthese compounds are intended as intermediates for the synthesis ofsteroids having the C/D- trans-orientation, this technique is notparticularly desirable. Although the ratio of B- to a-orientation fallsto about 1:1 at neutral conditions when hydrogenating a compound whereinZ is carbonyl, it is preferred to hydrogenate a 7B-alcohol or ester offormula la-2 because the products of this hydrogenation arepredominantly the 6a/9a(l0a)-trans-compounds. Compounds of formula la-3when subjected to the hydrogenation yield a ratio of B- to a-orientationin between that of the compounds of formula la-l and that of thecompounds of formula la-2. When monoenes of formula Ib-l havingCID-trans configuration are desired, it is preferable to first reducethe dienone of formula la-l to a corresponding hydroxy compound offormula la-Z prior to the catalytic hydrogenation. Following thecatalytic hydrogenation the carbonyl moiety in formula lb-l can beregenerated by conventional means, such as oxidation with chromiumtrioxide.

The monoene compounds of formula lb prepared by the abovedescribedhydrogenation contain at least three asymmetric centers. at positions 3,on and 911 when m is one and at positions 3, 6a and 1011 when m is two.With respect to these three centers there are thus cight antipodalconfigurations possible. By virtue of the unique asymmetric induction ofthis invention, proceeding from a racemic starting material of formulaII, lla or llb only four of these antipodes of formula lb are preparedand proceeding from an optically active starting material of formula II,lla, llb or llb-l only two of these antipodes of formula lb areprepared. Moreover, by the above-described hydrogenation of thisinvention and by appropriate selection of the 7- substituent in thediene of formula la subjected to the hydrogenation there canpredominantly be prepared the desired 6a,9a-(la)-trans-stereo-configuration. Thus, the eventual obtention of the moredesired l3B-C/D-trans-configuration in the ultimate steroidal productsis rendered more facile by the stereoselective reactions provided bythis invention.

Illustrative examples of the monoenes of formula lb includeoctahydrocyclopenta[f][ l ]-benzopyran-7( 8H )-one; 3,6a,8-diethyl-l,2,3,5,6,6a,9,9aoctahydrocyclopenta[f][ l ]-benzopyran-7(8l-I)-one;3,6aB-dipropyl-l,Z.3,5,6,6a,9,9aoctahydrocyclopenta[f]l l lbenzopyran-7(8H )-one; 3,- 6aB-dimethyl-7B-hydroxy-l ,2,3,5,6,6a,7,8,9,9a

decahydrocyclopenta[f][ l l-benzopyran; 7/3-acetoXy 3,6aB-dimethyl-l,2.3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][ l lbenzopyran; 7B-hydroxy-3,6aB,7a-trimethyll ,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][ l]benzopyran;3,6a[3,7atriethyl-7B-hydroxy-1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][1 ]benzopyran; 3,6afidimethyl-l,2,3,5,6,6a,8,9,lO,l0a-decahydro-7H-naphtho-[2,1-b]pyran7-one; 6aB-methyL3-(4- oxopentyl )-l,2,3,5,6,6a,9,9a-octahydrocyclopentalffl l ]benzopyran-7(8H )-one;6a/3-ethyl-3- (4-oxopentyl)-l,2,3,5,6,6a,9,9aoctahydrocyclopenta[f][ l]-benzopyran-7(8H )-one;3-[(4,4-ethylenedioxy)pentyl]-6a,B-methyll,2,3,5,6,6a,9,9a-octahydrocyclopenta[f][l ]benzopyran-7(8l-l)-one;3-(4-t-butoxypentyl)-6aB-methyll,2,3,5,6,6a,9,9a-octahydrocyclopentalf][l lbenzopyran-7(8H)-one;3-(4-hydroxypentyl)-6aB-methyll,2,3,5,6,6a,9,9a-octahydrocyclopentalf][l l-benzopyran-7( 8H )-one,3-(4-hydroxypentyl)-6aB-methyll,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][l benzopyran-7-ol, 6aB-ethyl-3-(4-hydroxypentyl)-l,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][ l benzopyran-7-ol and thelike.

The final reaction of applicants general process for the compounds ofthis invention is the conversion of the monoene of formula lb to theperhydro compound of formula 10 by reaction of the monoene with acompound having the formula:

R OH

Vlll

wherein R is as previously defined. That is, the monoone of formula lbis reacted with water, a primary alco hol, or a carboxylic acid. Thisreaction is catalyzed by 3,6aB-dimethyl-l,2,3,5,6,6a,9,9a-

mineral or organic acids, for example, hydrochloric acid, phosphoricacid, sulfuric acid, para-tolucnesulfonic acid, and the like. Sulfuricacid is the preferred acid catalyst, and water the preferred reactant.Although not necessary, it is desirable to conduct this reaction in thepresence of an added solvent, paticularly in the event the compound offormula VIII is water. In this case, it is desirable to employ a solventwhich is both miscible with water and a solvent for the monoene offormula lb. Solvents of this nature include acetone, tert.butanol,dioxane, and the like. The reaction temperature is not critical, andambient temperature is normally employed, although higher and lowertemperatures could be employed if desired.

In addition to the addition of the R OH compound, this step effects theconversion of a ketalized side chain such as the3-[(4,4-alkylenedioxy)pentyl]-group, if present, to the3-(4-oxopentyl)-group.

As with the compounds of formulae la-l and lb-l the compounds of generalformula lc wherein Z is carbonyl:

wherein Y, R,, R2, R R1 and m are as previously defined, are readilyconverted to their corresponding alcohols:

wherein Y, R R R R R and m are as previously defined,

or the ,8hydroxy-a-hydrocarbyl compounds:

perhydrocyclopentalf]l l ]benzopyran-7-one;(4amethoxy-3,baB-diethyl4a-hydroxyperhydro' cyclopentalfll l]benzopyran-7-one. 3-[4,4-( 2',3

butylenedioxy-pentyl]-6a/3-ethyl-4a-hydroxyperhytlrocyclopenta[f] llbenZopyran-7-one, 421,78-dihydroxy-S,6a/3-dimethyl-perhydrocyclopentalf][ llbenzopyran;4a,7B-dihydroxy-3,6a,8-7a-trimethylperhydrocyclopentalf][ l9-benzopyran;4a,7B- di( acetoxy J 3,(raB-dimethyl-perhydrocyclopentallfll llbenzopyran; 4a.7B-di(acetoxy)-3,6aB-dimethylperhydronaphtho l 2, l -blpyran; 4a-hydroxy-6al3- :methyl-3-l4-oxopentyl perhydrocyclopenta[f][ llbenzopyran-7-one; 3-[(4,4- ethylenedioxy) pentyl]-4a-hydroxy-oafi-methylperhydrocyclopentalflll lbenzopyran7-one',3-(4-tbutoxypentyl)-4a-hydroxy-6aB-methylperhydrocyclopentalfll llbenzopyran-7-one; 4ahydroxy-3-l 4-hydroxypentyl)-6aB-methylperhydrocyclopentalffl l lbenzopyran-7-one, 3-(4-hydroxypentyl)-6a[3-methylperhydrocyclopentalffl llbenzopyran-4a,7-diol, 3-(4- hydroxypentyl)6aB-ethylperhydrocyclopenta[f][ llbenZopyran4a,7-diol,6aB-methyl-3-(4-oxopentyl)- perhydrocyclopentalffl l]benZopyran-4a,7-diol, and the like.

Although in the various compounds of formula I, as well as theirprecursors of formulas ll, [la and llb, the

symbol Y comprehends a 3-oxobutyl moiety, it should be noted that it isnot preferred to work directly with such oxo-substituted compounds. Thisis because in many of the reaction steps utilized herein such an oxomoiety would itself be affected. Accordingly, it is preferred to protectsuch an oxo moiety and regenerate the 0x0 moiety from its protected format any desirable stage of the reaction sequence. Protection of the oxomoiety can effected according to means known per se. Similarly.regeneration of the oxo moiety from its protected form can be effectedby means known per se. Thus, one preferred method of effectingprotection of the oxo moiety is to convert it to its ketal by reactionwith an alkanediol in a known manner. Advantageous results are obtainedwhere protection of the oxo moiety is effected at an early stage in thesynthesis. An especially preferred alkanediol is butanediol whichaffords excellent resistance to attack by nucleophilic reagents. Whenbutanediol is employed, R and R when taken together are for example,2,3-butylenedioxy. Similarly, an oxo moiety can be converted to itsdithia ketal by reaction with dithioethane in a known manner, forexample, in acetic acid at room temperature and in the presence of borontrifluoride. Moreover, a monothia ketal can similarly be prepared in aknown manner, for example, by reaction of the 0x0 moiety withZ-mercaptoethanol in dioxane at room temperature in the pres ence ofZinc chloride and sodium sulfate. Also, the monoaza ketals can beprepared in a known manner, for example, by reaction of the oxo moietywith 2- hydroxyethylamine in the presence of acid. Finally, the 0x0moiety can be reduced to the corresponding hydroxy compound which canthen be etherified or esterified. As indicated above, the 0x0 moiety canbe regenerated from its protected form at any desired stage of thereaction sequence. Thus, it can be readily produced by hydrolysis of thealkylenedioxy ketals in a known manner. Similarly, it can be regeneratedfrom the dithia ketal in a known manner, for example, by treatment withphenylmercuric chloride and calcium carbonate in ethanol or by treatmentwith dioxane in methanolic hydrochloride. Also, it can be regeneratedfrom a monothia ketal in a known manner, for example, by treatment understrong acidic conditions, for example, by treatment with aqueoussulfuric acid in dioxane or hydrochloride in acetic acid. Moreover, itcan be regenerated from a monoaza ketal in a known manner, for example,by treatment with a strong aqueous acid. Also, ethers and/or esters canbe reconverted to the free hydroxy group which in turn can be oxidizedto give the oxo moiety.

As indicated above, the tricyclic compounds of this invention are usefulas intermediates for the preparation of various steroid compounds,depending upon the nature of Y. For example, compounds wherein Y ishydrogen or alkyl lead to 9/3,l()a-steroids or IOa-steroids. whereascompounds wherein Y is 3-substitutedbutyl. lead to l9-nor-steroids ofthe normal series, as illustrated by the following reaction scheme.

where R is hydrogen or alkyl; R is lower alkyl l the 3-ketulbutyl, oretherificd 3-hydroxybutyl, by Contact remaining symbols are as above. 65with such oxidizing agents as chromic acid, potassium in the first stepof this reaction scheme the comdichromute, or potassium permzmganante.Jones reapound of formula [C is oxidized to form hicyclie comgent(chromic acid, sulfuric acid and acetone), or a pound ofthc formula Xwherein Y is hydrogen, alkyl, chromic acid-acetic acid mixture arepreferred as oxidizing agents. The nature of Z is unchanged in this reaction, except when Z is hydroxymethylene [CH (OH 1. In this instance,unless the hydroxyl group is protected, as by formation of a lower acylester, it is okidized to form a carboxyl group. Similar oxidation iseffected when compound llc) contains as Y a 3- hydroxybutyl group. Ahydroxylated product is readily obtained, however, by hydrolysis of aproduct ester. The reaction temperature is not narrowly critical, andtemperatures in the range of from C. to about 75C. are suitable,although ambient temperatures are preferred.

ln the second step, bicyclic compound (X) is treated with acid or baseto effect cyclization to (XI). In this reaction, it is preferred thatthe water of reaction be rermoved, as by refluxing the reaction mixturewith an azeotroping agent in the presence of a strong acid andseparating the water from the condensate. Suitable strong acids aresulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like.Alternatively, base catalyzed dehydration can be utilized, for example,by refluxing the compound (X) in the presence of methanolic sodiumhydroxide. i

The hydrogenation of cyclo-olefin XI to tricyclic compounds XV or Xll ispreferably effected with a noble metal catalyst, e.g., apalladium-charcoal catalyst or a rhodium catalyst. In formula XV Rrepresents hydrogen or alkyl. Thus, when compounds of formula XI whereinY represents hydrogen or alkyl are hydrogenated, compounds of formula XVare obtained, whereas when compounds of formula XI wherein Y representsR5CH2C(R3,R4)CH(RH) CI-l(Rr.-,), hydrogenation yields compounds offormula XII. Hydrogena tion products of formula XI are converted toretrosteroids by base catalyzed reaction with methyl vinyl ketone toyield a 9B,l0a-androst-4-ene-3-one of formula XVIII. The conversion ofcompounds of formula XI to compounds of formula XV and of the latter tocompounds of formula XVIII are described in greater detail in BelgianPat. No. 663,l97.

Compounds of formula XI wherein Y is R can also be directly reacted withmethyl vinyl kctone yielding na S-hydroxy-tetracyclic compound offormula XVI. These latter compounds can then be subjected to dehydrationfollowed by hydrogenation or to hydrogenation followed by dehydration toyield 9-,l0aor I00:- steroids of formulas XVII and XVIII. Theseprocedures are described in greater detail in NetherlandsOctrooiaanvrage No. 6412939. Still other methods of utilizing compoundsof formula XI are described in the literature and other patents.

In those compounds of formula XI wherein Y is a 3- substituted butylradical, catalytic hydrogenation over a noble metal catalyst such aspalladium gives a l9-n0rsl.5-seco compound of formula XII. The3-substituted butyl radical is then converted to a 3-oxobutyl radical,-

thus giving a compound of formula XIII.

The conversion of the 3-substituted butyl radical of the compound offormula Xll to the 3-oxobutyl radical of the compound of formula XIIIcan be effected for each particular meaning of R and R in a manner knownper se as described hereinabove for generation nf a .l-oxobutyl moietyin compounds of formula I. W hen R and R taken together arealkylenedioxy, the conversion of compounds of the formula XII tocompounds of the formula Xlll proceeds directly in the presence of acid,e.g. hydrochloric acid or sulfuric acid and acetone at room temperature.

R15 R i wherein R R R R R Z and m are as above.

Exemplary of the compounds of this formula is6219atrans-2-methyl-6aB-ethyl-2,3,4,4b,5,6,8,9,9a.9b.l0.lldodecahydrocyclopenta [5,61naphthol 2.1 -b]pyran- 7(6aH)-one.Cyclization to the enol ether of formula XIX can be effected bytreatment of the alkoxy substituted derivatives of formula Xll with acidand heat in a solvent such as for example, benzene or toluene. Suitableacids for the cyclization step are p-toluenesulfonic acid, hydrochloricacid, phosphoric acid, potassium bisulfate and the like. Thiscyclization is preferably effected at the reflux temperature of thereaction medium although temperatures from between to l3() are suitable.

Further reaction of this novel class of enol ethers by treating with anagent R OI-l where R is hydrogen or lower alkyl, can be accomplishedutilizing the same conditions described previously for the reaction ofcompounds of formulae lb and VIII e.g. preferably hydration with acidsuch as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid and thelike, in the previously named solvents at room temperature yieldscompounds of the formula:

wherein R R R R R R Z and m are as above.

Exemplary of compounds of this formula is 6a,9atrans-2methyl-6aB-ethyl-7-oxoperhydrocyclopental 5.61-naphthol 2, l-b]pyranl la-ol.

The compounds of formula XX can be further re acted by an oxidationprocess to produce the diketone compounds of structure XIII. Moreover,where R in formula XX is ethyl, i.e., 6a9a-trans-2-methyl-6aB-cthyl-7-oxo-perhydrocyclopenta-[5,6]naptho[2,lb]pyran-l la-ol, theoxidation reaction affords the novel compoundl0[3-oxo-butyl]-l8-methyl-l9-nordesA-androstan-S,l7-dione. Exemplary ofthe suitable oxidizing agents for the reaction, are chromic acid andpotassium dichromate. Jones Reagent (chromic acid, sulfuric acid andacetone) is an especially preferred reagent for this purpose. Thereaction is carried out in the presence ofa mineral acid such ashydrochloric acid or sulfuric acid at room temperature.

Cyclization of the compounds of formula XIII can then be effected toyield l9-nor-androst-4-ene-3-one of the formula XIV. The cyclizationreaction of com pounds of formula XIII to compounds of formula XIV canbe effected by treatment of the compound of formula XIII with acid orbase. In this reaction it is pre- 2( ferred that the water of reactionbe removed, as by re-' fluxing the reaction mixture with an azeotropingagent in the presence of a strong acid and separating acid,p-toluenesulfonic acid, potassium bisulfate and the like. Alternatively,base-catalyzed dehydration can be utilized, for example, by heatingcompound XIII in the' presence of methanolic sodium hydroxide orpotassium t-butylate in t-butanol to about 50C. Moreover, where R informula XIII is ethyl, for example, l0-[3-oxobutyl l S-methyll9nor-desA-androstan-5,l 7-dione,

gon-4-ene-3-one). Exemplary of the suitable alkynylating agents toeffect the conversion to norgestrel are the alkali acetylides such aslithium acetylide, potassium acetylide, sodium acetylide, etc. Thereaction is carried out in the presence of liquid ammonia in a suitablesolvent system such as for example, benzene 0r toluene. The alkynylationis effected preferably at the reflux temperature ofthe reaction mediumalthough temperatures from between -60 to 30 are suitable. Exemplary ofother suitable reagents to effect the acetylenic addition are lithiumacetylide ethylenediamine complex in a dimethylformamide solvent andGrignard analogs such as mono and bis acetylene-magnesium halides. Theacetylene addition, known with l3-methylsubstituted steroids, issimilarly effected with the more bulky l3-ethyl-substituted steroidnotwithstanding the increased steric hindrance in the latterconfiguration.

The above and other methods for utilizing compounds of formulas XII andXIII as intermediates in syntheses of steroidal materials are describedin published patents and in the literature, such as French Pat. Nos.l,364,556; 1,452,898; 1,432,569 and 1,465,400.

In an alternate procedure not depicted in the subject reaction schemecertain compounds of formula XI wherein Y is 3-hydroxybutyl or an etheror ester protected derivative thereof can be converted to enol ethers offormula XIX via novel dienol ethers of formula XXV according to thefollowing scheme:

wherein Z,R ,R,-,,R ,R, R and R, are as above and R',; is hydrogen,lower alkyl, acyl, monocyclic carbocythe cyclization process yields thenovel l8-homo di- ,5 clic aryllower alkyl or a radical of the formulaketo compound l3B-ethyl-gon-4-ene-3,l7-dione.

Compounds of formula XIV can be selectively alkynylated by a suitableorgano metalic acetylide affording norgestrel(lSB-ethyl-l7(x-ethynyl-l7-hydroxywherein each of R2", R and Rindependently is lower alkyl.

It is to be understood that compounds of formula XI-a where R' is otherthan hydrogen, lower alkyl or acyl can be readily prepared fromcompounds of formula XI where R is hydroxy by reacting the lattercompound with a halo derivative of the radical to be introduced such asa monocyclic carbocyclic aryl lower alkyl halide or where X is halousing conditions otherwise well known in the art for such reaction.

As used above the term monocyclic carbocyclic aryl denotes a phenyl orsubstituted phenyl radical. Substituted phenyl radicals have one or moreof the same or different substituents attached to any position availablefor substitution. Substituents on the aryl group may include. forexample, lower alkyl, e.g. methyl, ethyl and the like; etherifiedhydroxyl, such as, lower alkoxy, e.g., methoxy. cthoxy, and the like.The term monocyclic carbocyclic aryl-lower alkyl comprehends, forexample, phenyllower alkyl, e.g., benzyl, l-phenylethyl, 2- phenylethyl,and the like included aryl substituted derivatives thereof.

lln step Ia) of the subject reaction scheme the 10-[3-:substitutcd-alkyll-Al-des A-steroids of Formula KI-a are cyclized toyield the novel dienol ether compound of formula XXV. The cyclization issuitably effected by the application of heat in the presence of amineral acid, such as sulfuric acid or hydrogen halides, cg,hydrochloric acid; or an organic acid, preferably an aryl sulfonic acidsuch as benzene sulfonic acid or p-toluene sulfonic acid. Thecyclization reaction can be conducted in any suitable inert organicsolvent, preferably however, a hydrocarbon such as benzene or toluene isemployed. The reaction is conveniently carried out at the refluxtemperature of the solvent although lower reaction temperatures can alsobe employed consistent with carrying out the reaction in a minimum oftime without undue difficulty. When R in the compounds of formula XI-ais hydrogen the aforesaid cycliization can be effected by theapplication of heat alone, acid treatment alone or a combination ofboth.

In step lb) of the subject scheme dienol ether compounds of formula XXVare converted into cnol ether compounds of formula XIX by a novelselective hydrogenation procedure. The hydrogenation can be suitablyeffected by employing a nobel metal catalyst such as, palladium.platinum and rhodium with the preferred catalyst being palladium. It ispreferred to deposit the catalyst on a suitable support material, carbonbeing found to be most convenient for the purpose. The hydrogenation issuitably conducted in the presence of an inert organic solvent,preferably a hydrocarbon such as benzene or toluene. Ambient conditionsof room tempcrature and atmospheric pressure are generally preferred toavoid significant hydrogenation of the A*"" bond. The hydrogenation mustbe effected under basic conditions. A most suitable base has been foundto be u trl-lower alkylamine, such triethylamine.

Compounds of formulae XI, XIV, XVII, XVIII, XIX and XX wherein Z iscarbonyl can be converted into corresponding pregnane compounds, i.e.,compounds in which Z is of the formula by known procedures. Thus, forexample, l9-nor-l4fiandrost-4-ene-3,l7-dione can be converted intol9-nor-l4B,l7a-progesterone and desA-androst- 9-ene- 5,l7-dione can beconverted into desA-pregn-9- en-5-one. These procedures for convertingandrostl7-ones into pregnanes are best effected if all carbonyl groupsother than that in the l7-position are initially protected.

As has been pointed out above, the products of this invention areproduced in the form of various optically active antipodes, which can becarried through the entire reaction sequence, or which can be resolvedat suitable places during the reaction sequence. For example, at anystage wherein a compound having a secondary hydroxy] group is present,such as hydroxytetrahydropyran (IV), or any of the hydroxy compounds offormula I, one can react the secondary alcohol with a dicarboxylic acidto form a half-ester. Suitable dicarboxylic acids include lower alkyldicarboxylic acids such as oxalic acid, malonic acid, succinic acid,glutamic acid, adipic acid, or aromatic carboxylic acids such asphthalic acid. The resulting half-ester is then reacted with anoptically active base, such as brucine, ephed rine, or quinine, toproduce a diastereomeric salt. The salts, after separation, are thenreadily reconverted to optically active alcohols. As an alternative, thesecondary alcohol can be reacted with an optically active acid, forexample, camphorsulfonic acid. The resulting diastereomeric esters arethen separated and reconverted to the alcohols.

It is preferred that the resolution be effected at some stage in thesynthesis of alkeri-3-one, as by the abovementioned resolution ofhydroxytetrahydropyran (IV). In a more preferred technique opticallyactive S-alkyl- 5-valerolactone is obtained from S-alkyl-S- oxopentanoicacid via known microbiological processes. The S-form of this lactone isthe preferred form for use in accordance with this invention. In a thirdmethod, the racemic lactone can be hydrolyzed to the correspondinghydroxy acid, which is then resolved by treatment with an opticallyactive base in the manner described above. Still other methods will beapparent to those skilled in the art. Resolution at such early stages inthe overall process described herein is highly preferred because of theimproved efficiency in the production of steroids having a desiredstereo configuration. Because the stereo-configuration is retainedthroughout the synthesis of alken-3-one (ll and further, because thecondensation of alken-3-one or variant (ll, Ila or lIb) withcycloalkanedione (III) is stereo-specific, one, by proper selection ofstereoisomers at these early stages, can ensure that substantially allof the tricyclic compounds of this invention and the steroids derivedtherefrom have a selected stereo-configuration. Thus, by this technique,the production of compounds of the undesired configuration is minimizedor prevented entirely, with an attendant increase in the efficiency ofthe production of compounds of the desired configuration.

In the claims, all compounds shall be construed to include,independently, the racemic form of the compound and independently, eachenantiomeric form, i.e., the d and l configurations unless specificallyindicated otherwise.

The following examples are illustrative. All temperatures are in degreeCentrigrade and all products having centers of asymmetry are racemicunless specifically indicated otherwise.

Example 1 a. A mixture of 38 grams of 2-methylcyclohexane- 1,3-dione, 51grams of sodium hydroxide, and 450 milliliters of water was hydrogenatedover Raney nickel catalyst at a maximum temperature of 140C. and amaximum pressure of 750 psi. The reaction mixture was filtered and thefiltrate, containing sodium 5- hydroxyheptanoate, was acidified withconcentrated hydrochloric acid (to a pH of l), and then refluxed for 30minutes. The resulting solution was cooled and filtered. The filtratewas extracted with three l-liter portions of benzene and the combinedbenzene extracts, after washing with water, drying over sodium sulfate,and evaporation, yielded 26 grams of S-ethyl-S- hydroxy-valeric acidlaetone.

b. A suspension of5.2 grams oflithium aluminum hydride in 250milliliters of anhydrous ether was added with stirring over one hour toa solution of 64 grams of S-ethyLS-hydroxyvaleric acid laetone in 500milliliters of anhydrous ether maintained at 05C. and under a nitrogenatmosphere. After the addition of 250 milliliters of 3N sulfuric acid,the reaction mixture was extracted with three lOO-milliliter portions ofether. The combined ether extracts were then washed with twolOO-milliliter portions of sodium bicarbonate solution, then with twoISO-milliliter portions of water. After drying over sodium sulfate, theetheric solution was evaporated at 45C. under vacuum to yield 57.1 gramsof 6-ethyl-2-hydroxytetrahydropyran.

c. To 7.6 grams of magnesium in 7 milliliters of anhydroustetrahydrofuran containing a few drops of ethyl bromide and a fewmilligrams of iodine maintained at 45-48C. was added, over a four-hourperiod, 120 mil liliters of a 20.8 weight per cent solution of vinylchloride in tetrahydrofuran. The resulting reaction mixture was cooledto 30C. and a solution of 13 grams of 6- ethyl-Z-hydroxytetrahydropyranin 40 milliliters of tetrahydrofuran was added. After standingovernight, there was added ice and ammonium chloride. Extraction of theresulting mixture with three 250-mil1iliter portions of ether, washingwith three l00-mil1iliter portions of sodium chloride, drying oversodium sulfate, and evaporation gave 16 grams of 3,7-dihydroxy-lnonene.

d. To a solution of 25 grams of l-nonene-3,7-diol in 1250 milliliters of1,2-dichloroethane was added 0.25 gram of hydroquinone and 300 grams ofmanganese dioxide. The resulting slurry was stirred vigorously for onehour without heating, during which time the reaction temperature rose toabout 30C. The resulting reaction mixture was filtered and the manganesedioxide filter cake was washed thoroughly with 500 milliliters of1,2-dichloroethane. The combined filtrates were evaporated in vacuo at40C. to yield 17.3 grams of 7-hydroxy-l-nonen-3-one. This compound isreacted with hydrogen chloride to produce lchloro-7- hydroxynonan-3-one,with dimethylamine to producel-(N,N-dimethylamino)-7-hydroxynonan-3-one, with water to producel.7-dihydroxynonan-3-one, or with ethanol to producel-ethoxy-7-hydroxynonan-3-one.

Example 2 Employing procedures similar to those described in Example 1,except that cyclohexane-l,3-dione is substituted forZ-methylcyclohexane-l .3-dione, 7-hydroxyoct-l-en-3-one is produced.

Example 3 Employing procedures similar to those described in Example 1,except that 2-ethylcyclohexane-l,3-dione is substituted for2-methylcyclohexane-l,3-dione. 7-hydroxydec-l-en-3-one is produced.

Example 4 A 20 per cent solution of diisobutyl a1 ninum hydride in 31.4milliliters of toluene was added over a 30- minute period to a solutionof 5 grams of L-(-)-5- pentyl-S-hydroxy-valeric acid laetone in 50milliliters of toluene at -C. After workup of the resulting reactionmixture as described in Example l(b), there was obtained 5 grams ofpractically pure optically active 6- pentyl-2-hydroxytetrahydropyran.

To a solution of this product in 20 milliliters of tetrahydrofuran wasadded at 30C. a solution of vinyl magnesium chloride in tetrahydrofuranprepared from 3.5 grams of magnesium and excess vinyl chloride in themanner described in Example 1(c). After hydrolysis of the reactionproduct with an ammonium chloride-ice mixture, followed by extractionwith ether, there was obtained 5.72 grams of3(R,S),7(S)-dihydroxy-ldodecene as an oil. After crystallization fromisopropyl ether-pentane at 0C., the diol melted at 65.5-67.5C. and hadan optical rotation [a],, "==+5.9 as determined from a l percentsolution in chloroform.

A solution of 5.22 grams of the diol in 1,2- dichloroethane was stirredwith 63 grams of manganese dioxide in the presence of 50 milligrams ofhydroquinone for one hour. After filtration to remove the manganesedioxide, washing with additional dichloroethane and ether, andevaporation of the filtrate at 30C., there was obtained 3.98 grams ofoptically active 7(S)-hydroxy-l-dodecen-3-one.

Example 5 A solution of racemic 7-hydroxy-l-nonen-3-one [21.3 g.; crudeobtained as in Example l(d)] in hexane (200 ml.) was treated for 15hours at 25C. with a solu tion of (-)-a-pheny1ethylamine (11.5 g.) inhexane ml.). The reaction mixture was then purified by chromatography onalumina (660 g.). Elution with hexane first gave unpolar by-products.Hexane-ether- (4:1 (1:1), and straight ether then eluted *2-[2-(1-phenylethylamino )ethyl ]-6-ethyl-Z-tetrahydropyranol obtained in solidform after evaporation of the solvents.

Example 6 To a solution of the 2-[2-(lphenylethylamino)ethyll-6-ethy1-2-tetrahydropyranol (prepared andpurified as described in Example 5;

120 ml.) Thus. the oxalate of 2-[2-(1-phenylethylamino)ethyll-6(S)-ethyl-2- tetrahydropyranol was obtained,m.p. 123128, 1101],, 28.2 (v 1.0; methanol).

Example7 To 20 g. of magnesium turnings in a 500 ml. flask equipped withdry-ice condenser. thermometer. and dropping funnel. ml. oftetrahydrofuran was added followed by dropwise addition of vinylchloride solution 1200 ml.; 26% solution in tetrahydrofuran) while theoil bath in which the flask was immersed was maintained at 70. The vinylchloride was added at such a rate so that the reaction temperatureremained at l6-52"C. lodine vapor and methyl iodide were used toinitiate the reaction.

Upon completion of the addition of the vinyl chloride. the reactionmixture was cooled to -5. and 6- l44-(ethylenedioxy)-pentyl]tetrahydrofuran-2-ol 144.63 g.) dissolved in150 ml. tetrahydrofuran was added dropwise to the Grignard reagent at 5to 0C. The resulting mixture was stirred overnight atroom temperature.

The solution was then treated with ice and ammonium chloride solution(200 ml. and the mixture ex tracted three times. each time with 500 ml.of chloroform. The organic phase was washed once with ammonium chloridesolution and twice with water, and then dried over anhydrous sodiumsulfate. Removal of the solvent in vacuo afforded crude11.11-ethy1enedioxylldihydroxy-l-dodecene as pale yellow liquid whichsolidified upon refrigeration.

A sample of the crude product was recrystallized once from isopropylether-hexane to give clusters of colorless needles which upon threeadditional recrystallizations from the same solvent provided 1 1,1 1-ethylenedioxy-3,7-dihydroxy-l-dodecene which melted at 5254.

A solution of 22.0 g. of 11.11-ethylenedioxy-1- dodecene-3.7-diol inbenzene (600 ml.) and diethylamine ml.) was treated under vigorousstirring with manganese dioxide (108 g.) at 25C. After stirring for 18hours at room temperature. the manganese dioxide was filtered off andwashed with benzene. AFter evaporation of the filtrate crude2-(2-diethylaminoethyl)6- lj 4.4-ethylenedioxypentyl)-2-tetrahydropyranol was obtained.

A sample of the crude l 1,1 l-ethylenedioxy-3,7-dihydroxy I -dodecane10g; prepared as described above) was dissolved in dichloroethane (250ml.), and to this solution activated manganese dioxide g.) was added.The mixture was stirred for 1 hour at room temperature, filtered, andthe filter cake washed three times. each time with 250 ml. ofdichloroethane. Concentration of the combined filtrate afforded crude l1;- ll 1-ethylenedioxy-7-hydroxy- 1 -dodecen-3-onc.

Example 8 A mixture of 8.3 grams of 7-hydroxy-1-nonen-3-one. 7' grams of2-methylcyclopentane-l.3-dione. 0.1 gram of hydroquinone, 4.2milliliters of pyridine, and 42 milliliters of toluene was refluxedunder a nitrogen atmosphere for 2 hours employing a Dean-Starkwatercollection apparatus. The reaction solution, after cooling. wasfiltered to recover unreacted 2-methylcyc1opentane-1,3-dione. Thefiltrate was evaporated to dryness, yielding 9.78 grams of crude 3ethy1-6aB-methy1- 1.2.3,5,6,6a hexahydrocyclopenta[f}[1]benzopyran-7(8H)-one. A mixture of the crude product. 1 gram of charcoal, andmilliliters of ether was refluxed for 5 minutes. After decantation. theresulting solution was concentrated and 20 milliliters of hexane wasadded to cause crystallization. A first crop of 3.88 grams was obtainedwhich melted at 96-99C. After concentration of the mother liquor andcrystallization from a cold diisopropyl ether/hexane mixture, a secondcrop of crystals melting at 1()()1()3C. was obtained.

Employing similar procedures 3-ethyl-6aB-methyl- 1,2,3,5,6,6a,hexahydrocyclopentalfll l ]benzopyran- 7(8H)-one is prepared bysubstituting 1-chloro-7- hydroxynonan-S-one for the7-hydroxy-1-nonen-3-one.

Example 9 A mixture of 16.2 grams of 7-hydroxy-l-nonen- 3-one. l 1.5grams of 2-methylcyclopentane-l .3-dione. 210 milliliters of xylene. andmilliliters of acetic acid was refluxed for 1 hours. After evaporation,the crude reaction product, weighing 27.9 grams. was extracted with two-mi11i1iter portions of benzene. The remaining residue, which weighed1.7 grams, was unreacted 2-methylcyclopentane-l.3-dione. The benzeneextracts were combined and evaporated to yield 25 grams of crudeproduct. A solution of this product in hexane was filtered throughalumina and, after evaporation of the hexane and crystallization of theproduct from a hexane-pentane mixture. there was obtained 16.6 grams of3-ethy1-6afi-methyl-1,2,3,5.6,6ahexahydrocyclopenta[f][1]benzopyran-7(8H)-one, melting point 104-l06C.

Employing similar procedures 3-ethy1-6aB-methyl-1,2,3,5,6,6a-hexahydrocyclopentalf][ l ]benzopyran- 7(8H)-one isprepared by substituting 1-(N.N- dimethylamino)-7-hydroxynonan-3-one forthe 7-hydroxy-1-nonen-3-one.

Example 10 A mixture of 1.56 grams of 7-hydroxy-1-nonen- 3-one, 1.12grams of 2-methylcyclopentane-1,3dione, and 50 milliliters of toluenewas refluxed for 6 hours. Workup of the reaction mixture in the mannerdescribed in Example 9 yielded 3-ethyl-6aB-methyl-1,2.3,5,6.6a-hexahydrocyclopenta[f][1]benzopyran- 7(8H)-one.

Example 1 l A mixture of 1.56 grams of 7-hydroxy-l-nonen- 3-one, 1.12grams of Z-methylcyclopentane-l.3-dione, 16 milliliters of p-dioxane,and 80 milligrams of ptoluenesulfonic acid was reacted at 25C. for 22hours. Employing the work-up procedures of Example 9, there was obtained3-cthyl-6aBmethyl- 1 .2,3,5,6.6a hexahydrocyclopenta[f][ l]benzopyran-7( 8H )-one.

Example 12 A mixture of 1.56 grams of 7-hydroxy-1-nonen- 3-one, 1.12grams of 2-methylcyclopentane-l,3-dione, 0.16 grams of ptoluenesulfonicacid, and 16 milliliters of benzene was refluxed for 30 minutes andworked up as described in Example 9 to yield 3-ethy1-6a/3-methyl-

1. A COMPOUND OF THE FORMULA